Hydroxyurea appears to be a promising agent for the prevention of vascular occlusion in sickle cell disease (SCD). Current thinking holds that the clinical benefits of hydroxyurea are mediated by increases in Hb F concentration. Therefore, the current treatment strategy is to use maximally tolerated doses of hydroxyurea in order to achieve the maximimum Hb F response. However, several lines of evidence suggest that factors other than increased Hb F per se are also important. We hypothesize that a key effect of hydroxyurea is a marked reduction in the dense subpopulation of sickle RBC. We therefore propose to investigate whether titration of hydroxyurea dosage to this endpoint can achieve significant clinical benefits without the hematologic toxicity often associated with maximal doses, thus resulting in an improved risk:benefit ratio, better patient compliance and broader applicability to the patient population. We further propose to characterize the effects of this treatment strategy on a broad range of RBC, WBC and hemorheologic properties in SCD, and to determine its efficacy in treating several important vasoocclusive complications of SCD: painful crisis, pulmonary hypertension, renal insufficiency and leg ulcers. These investigations should provide an improved understanding of the physiologic effects of hydroxyurea in SCD, as well as give new insights into its clinical utility.